<div class="application article clearfix" id="description">
<p class="printTableText" lang="en">New Zealand Paient Spedficaiion for Paient Number 502786 <br><br>
WO 99/14184 PCT/US98/16652 <br><br>
-1- <br><br>
NOVEL STEREOSELECTIVE PROCESSES FOR THE PREPARATION OF GABAPENTIN ANALOGUES <br><br>
BACKGROUND OF THE INVENTION <br><br>
United States Patent Number 5,091,567, hereby incorporated by reference, covers a process for the preparation of gabapentin (1-aminomethyl-l-cyclohexane-acetic acid) <br><br>
h2n co2h which medicament is useful, for example, in the treatment of epilepsy. The process is illustrated by the scheme: <br><br>
\r <br><br>
Step (a) <br><br>
O <br><br>
O II <br><br>
+ (c2h50)2pch2c02c2h5 <br><br>
Step (b) <br><br>
h. .co2c2h5 o2n co2c2h5 <br><br>
H^ ^C02C2H5 <br><br>
\r <br><br>
+ ch3no2 <br><br>
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Step (c) <br><br>
°2n co2c2h5 <br><br>
Hn <br><br>
H <br><br>
h2n co2h <br><br>
.hc1 <br><br>
Step (e) <br><br>
h2n co2h h2n <br><br>
.HC1 <br><br>
basic ion exchanger co2h <br><br>
The instant invention provides a stereoselective synthesis for the ring-substituted analogs of gabapentin and to gabapentin itself. The advantages of the instant syntheses are: control of stereochemistry and no resolution is required at the end of the synthesis. <br><br>
SUMMARY OF THE INVENTION <br><br>
The invention encompasses a novel synthetic route for the preparation of 10 substituted gabapentin analogues The route enables the synthesis of certain single stereoisomers of individual alkylated gabapentin derivatives with a high degree of stereochemical purity. <br><br>
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The invention is outlined in the general route shown below. The first step involves conversion of a substituted cyclohexanone to an a,p-unsaturated ester via use of a trialkylphosphonoacetate or an (alkoxycarbonylmethyl)triphenyl-phosphonium halide and a base, such as sodium hydride, potassium hydride, 5 lithium- or sodium- or potassium-hexamethyldisilazide, butyllithium or potassium t-butoxide in a solvent such as tetrahydrofuran, dimethylformamide, diethylether, or dimethylsulfoxide at a suitable temperature in the range from -78°C to 100°C. <br><br>
The second step involves reaction of the a,P-unsaturated ester with nitromethane and a suitable base such as tetrabutylammonium fluoride, tetra-10 methylguanidine, l,5-diazabicyclo[4,3,0]non-5-ene, l,8-diazabicyclo[5,4,0]undec-7-ene, a sodium or potassium alkoxide, sodium hydride or potassium fluoride in a solvent such as tetrahydrofuran, diethylether, dimethylformamide, dimethylsulphoxide, benzene, toluene, dichloromethane, chloroform, or tetrachloromethane at a suitable temperature in the range from -20°C to 100°C. 15 The third step involves catalytic hydrogenation of the nitro moiety using a catalyst such as Raney nickel, palladium on charcoal or rhodium catalyst or other nickel or palladium containing catalyst in a solvent such as methanol, ethanol, isopropanol, ethyl acetate, acetic acid, 1,4-dioxane, chloroform or diethyl ether at a suitable temperature in the range from 20°C to 80°C. <br><br>
20 The final step involves a hydrolysis using hydrochloric acid and may also utilize a cosolvent such tetrahydrofiiran or 1,4-dioxane or other such inert water miscible solvent at a suitable temperature in the range from 20°C to reflux. <br><br>
Printed from Mimosa <br><br>
General scheme: <br><br>
O <br><br>
X <br><br>
(i) <br><br>
X <br><br>
-4- <br><br>
co2r <br><br>
(ii) <br><br>
intellectual property office of n.z. <br><br>
1 4 FEB 2002 RECEIVED <br><br>
o2n co2r <br><br>
X <br><br>
hci.h2n co2h hn <br><br>
(iv) <br><br>
o <br><br>
(iii) <br><br>
X <br><br>
X <br><br>
In one embodiment the invention provides a process for the preparation of a compound of formula <br><br>
HCl.H^N CO?H <br><br>
x1 <br><br>
ii <br><br>
T <br><br>
which comprises: <br><br>
a) adding 4-methylcyclohexanone to a mixture of sodium hydride suspended in dry tetrahydrofuran to which triethyl phosphonoacetate was added to produce a mixture; <br><br>
b) decanting the solvent from the mixture step a) above to produce an a,P-unsaturated ester; <br><br>
c) dissolving the ester from step b) above in nitromethane and heating the resulting mixture; <br><br>
d) dissolving the nitro ester from step c) above in methanol and shaking in the presence of H2 over a catalyst to produce the corresponding lactam; and <br><br>
(followed by page 4a) <br><br>
intellectual property office of N.Z. <br><br>
1 k FEB 2002 <br><br>
RECEIVED <br><br>
-4a- <br><br>
e) heating the product of step d) above to reflux in a mixture of HC1 and dioxan to produce a compound of formula II above and converting, if desired, to a pharmaceutically acceptable salt. <br><br>
In one embodiment the invention provides a process for the preparation of compound of formula which comprises: <br><br>
a) adding cis 3, 5-dimethylcyclohexanone to a mixture of sodium hydride suspended in dry tetrahydrofuran to which triethyl phosphonoacetate was added to produce a mixture; <br><br>
b) decanting the solvent from the mixture of step a) above to produce an a,P-unsaturated ester; <br><br>
c) dissolving the product of step b) above in nitromethane and heating the resulting mixture; <br><br>
d) dissolving the nitro ester from step c) above in methanol and shaking in the presence of H2 over a catalyst to produce the corresponding lactam; and e) heating the product of step d) above, a lactam, to reflux in HC1 and dioxan to produce a compound of formula III above and converting, if desired, to a pharmaceutically acceptable salt thereof. <br><br>
In one embodiment the invention provides a process for the preparation of compound of formula <br><br>
III <br><br>
hci.h2n co7h <br><br>
IV <br><br>
which comprises: <br><br>
(followed by page 4b) <br><br>
intellectual property office of n.z. <br><br>
. I <br><br>
RECEIVED <br><br>
1 4 FEB 2002 <br><br>
-4b- <br><br>
a) adding 3R 3-methylcyclohexanone to a mixture of sodium hydride suspended in dry tetrahydrofuran to which triethyl phosphonoacetate was added to produce a mixture; <br><br>
b) decanting the solvent from the mixture of step a) above to produce the corresponding a,p-unsaturated ester; <br><br>
c) dissolving the ester from step b) above in nitromethane and heating the resulting mixture; <br><br>
d) dissolving the nitro ester from step c) above in methanol and shaking in the presence of H2 over a catalyst to produce the corresponding lactam; and e) heating the product of step d) above to reflux in a mixture of HC1 and 1,4-dioxane to produce a compound of formula IV above and converting, if desired, to a pharmaceutically acceptable salt thereof. <br><br>
Unless the context clearly requires otherwise, throughout the description and the claims, the words "comprise", "comprising" and the like, are to be construed in an inclusive sense as opposed to an exclusive or exhaustive sense, that is to say, in the sense of "including, but not limited to". <br><br>
The following experimental procedures provide a novel route to be used to stereoselectively synthesize gabapentin and analogues thereof. This route provides access to pure stereoisomers. <br><br>
Example 1 below shows the route used to synthesize gabapentin itself. <br><br>
This route is also useful in the synthesis of compounds of formula <br><br>
DETAILED DESCRIPTION OF THE INVENTION <br><br>
NHo C02H <br><br>
I <br><br>
a pharmaceutically acceptable salt thereof or a prodrug thereof wherein A is a bridged ring selected from <br><br>
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-5- <br><br>
(1) <br><br>
(2) <br><br>
(3) <br><br>
(CRiR2)n /■ <br><br>
Rq <br><br>
R/i and <br><br>
(4) (5) <br><br>
wherein <br><br>
R] and R2 are each independently selected from hydrogen and methyl; <br><br>
R3 and R4 are each independently selected from hydrogen or methyl; <br><br>
n is an integer of from 1 to 4; and m is an integer of from 0 to 2. <br><br>
The route is further useful in the synthesis of compounds of formula nh2 co2r nh2 co2r or ii or a pharmaceutically acceptable salt thereof wherein: <br><br>
X is O, S, S(O), S(0)2, or NRi wherein Ri is hydrogen, straight or branched alkyl of from 1 to 6 carbon atoms, benzyl, -C(0)R2 wherein R2 is straight or branched alkyl of from 1 to 6 carbon atoms, benzyl, or phenyl, or -CO2R3 <br><br>
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wherein R3 is straight or branched alkyl of from 1 to 6 carbon atoms, or benzyl wherein the benzyl and the phenyl groups can be unsubstituted or substituted by from 1 to 3 substituents each independently selected from halogen, CF3, and nitro; and 5 R is hydrogen or lower alkyl. <br><br>
Example 2 below shows the use of a 4-substituted cyclohexanone to provide a pure trans gabapentin analog. <br><br>
Example 3 below shows the use of a disubstituted cyclohexanone. <br><br>
10 Example 4 below shows the use of a 3-substituted gabapentin analog to provide a pure cis product which is a mixture of enantiomers. The use of an enantiomerically pure 3-substituted cyclohexanone provides a pure product. <br><br>
General Route <br><br>
°2n co2r <br><br>
Jl <br><br>
(i) <br><br>
► <br><br>
hci.h2n co2h <br><br>
15 Reagents and conditions. <br><br>
(i) (R10)2P(0)CH2C02R, base (e.g., NaH, LiN(SiMe3)2, K,H BuLi) <br><br>
(ii) MeN02, base (e.g., Bu4N+F, Tetramethylguanidine, KF) <br><br>
(iii) Catalytic hydrogenation using, for example, Raney nickel or Palladium on charcoal) <br><br>
20 (iv) Hydrolysis using HC1 <br><br>
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-7- <br><br>
EXAMPLE 1 <br><br>
O <br><br>
C02Et q2N C02Et i. n <br><br>
HC1.H2!JJ C02H <br><br>
(iv) <br><br>
(i) (Et0)2P(0)CH2C02Et, NaH, THF <br><br>
(ii) MeN02, Bu4N+F, THF, 70°C <br><br>
(iii) Raney Ni, H2, MeOH <br><br>
(iv) HC1/H20 <br><br>
10 oc.B-unsaturated ester <br><br>
Sodium hydride (60% dispersion in oil, 1.16 g, 28.99 mmol) was suspended in dry tetrahydrofuran (40 mL) and cooled to 0°C. Triethyl phosphonoacetate (6.35 mL, 31.89 mmol) was added Once the effervescence had subsided the mixture was stirred at 0°C for 15 minutes. Cyclohexanone (3 mL, 15 28.99 mmol) was then added and the mixture allowed to warm to room temperature. After 1 hour the mixture was partitioned between 2N HC1 (50 mL) and diethyl ether (100 mL). The ether layer was collected, washed with brine, dried (MgS04), and the solvent removed in vacuo to give a clear oil which was <br><br>
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-8- <br><br>
purified by flash chromatography (silica, ethyl acetate:heptane 1:9) to yield 3.8 g (78%) of a colorless oil which was used without further purification. <br><br>
Nitro ester <br><br>
The a,P-unsaturated ester (1 605 g, 9.55 mmol) was dissolved in 5 tetrahydrofuran (30 mL) with nitromethane (1.03 mL, 19.1 mmol) and tetrabutylammonium fluoride (1.0 M in THF, 14 mL, 14.0 mmol) and the resulting mixture heated to 70°C. After 18 hours the mixture was diluted with ethyl acetate (60 mL) and washed with 2N HC1 (40 mL) followed by brine (40 mL). The organic phase was separated, dried (MgS04), and the solvent removed in vacuo. 10 The residue was purified by flash chromatography (silica, ethyl acetate:heptane, 1:9) to give 996 mg (46%) as a colorless oil. <br><br>
^H NMR 400 MHz (CDC13) 5: 1.27 (3H, t, J = 6Hz), 1.38-1.62 (10H, m), 2.54 (2H, s), 4.15 (2H, q, J = 6Hz), 4.70 (2H, s). <br><br>
MS (ES+) m/e: 230 ([MH]+; 78%), 170 (100%) <br><br>
15 IR thin film v (cm"1): 1031,1180, 1377,1548,1732,2935. <br><br>
C] iH19N04 calculated: C, 57.63%; H, 8.35%; N, 6.11% <br><br>
Found: C, 57.88%; H, 8.61%; N, 6.01% <br><br>
Lactam <br><br>
The nitro ester (935 mg, 4.08 mmol) was dissolved in methanol (40 mL) 20 and shaken over Raney nickel (catalytic) under an atmosphere of hydrogen gas (40 psi) at 35°C. After 18 hours the catalyst was removed by filtration through celite. The methanol was removed in vacuo to give 622 mg (100%) of an oil which crystallized on standing. <br><br>
]H NMR 400 MHz (CDCI3) 6:1.38-1.61 (10H, m), 2.18 (2H, s), 3.14 (2H, s), 25 5.61 (1H, br s). <br><br>
MS (ES+) m/e: 154 ([MH]+; 100%) <br><br>
IRthin film v (cm"1): 1252,1451, 1695,2925. <br><br>
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C9H15NO calculated: C, 70.55%; H, 9.87%; N, 9.14% Found: C, 70.46%; H, 9.72%; N, 8.97% <br><br>
10 <br><br>
Amino Acid Hydrochloride <br><br>
The lactam (608 mg, 4.0 mmol) was heated to reflux in a mixture of 6N HC1 (15 mL) and 1,4-dioxan (5 mL). After 4 hours the solvent was removed in vacuo and the solid residue recrystallized from a methanol/ethyl acetate/heptane mixture to give 682 mg (71%) of a white solid. <br><br>
*H NMR 400 MHz (d-6 DMSO) 8:1.12-1.51 (10H, m), 2.41 (2H, s), 2.91 (2H, s), 8.06 (3H, br s), 12.36 (1H, br s). <br><br>
MS (APCI) m/e: 172 ([MH-HC1]+; 100%) <br><br>
C9H1 gN02Cl calculated: C, 52.05%; H, 8.74%; N, 6.74%; CI, 17.07% <br><br>
Found: C, 51.97%; H, 8.77%; N, 6.63%; CI, 16.94% <br><br>
EXAMPLE 2 <br><br>
CO-vEt <br><br>
15 (1) (EtO)2 P(0)CH2C02Et, NaH, THF (ii) MeN02, Bu4N+F\ THF, 70°C <br><br>
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PCT/US98/16652 <br><br>
-10- <br><br>
(iii) Raney Ni, H2, MeOH <br><br>
(iv) HC1/H20 <br><br>
g.B-unsaturated ester <br><br>
Sodium hydride (60% dispersion in oil, 0.98 g, 24.45 mmol) was 5 suspended in dry tetrahydrofuran (50 mL) and cooled to 0°C. Triethyl phosphonoacetate (5.12 mL, 25 67 mmol) was added. Once the effervescence had subsided the mixture was stirred at 0°C for 15 minutes. 4-Methyl cyclohexanone (3 mL, 24.45 mmol) was then added and the mixture allowed to warm to room temperature. After 1.5 hours the solvent was decanted from the thick oil which 10 had formed and the oil washed with diethyl ether (3 x 50 mL). The decanted solvent and the ether washings were combined and washed with 2N HC1 (50 mL) followed by brine (50 mL), dried (MgS04), and the solvent removed in vacuo to give a clear oil which was used without purification. <br><br>
-Nitro ester <br><br>
15 The a,P-unsaturated ester (2.94 g, 16.15 mmol) was dissolved in tetrahydrofuran (20 mL) with nitromethane (1.75 mL, 32.3 mmol) and tetrabutylammonium fluoride (1.0 M in THF, 24 mL, 24.0 mmol) and the resulting mixture heated to 70°C. After 18 hours the mixture was diluted with ethyl acetate (60 mL) and washed with 2N HC1 (40 mL) followed by brine (40 mL). The 20 organic phase was separated, dried (MgS04), and the solvent removed in vacuo. The residue was purified by flash chromatography (silica, ethyl acetate:heptane, 1:9) to give 2.74 g (70%) as a colorless oil. <br><br>
!H NMR 400 MHz (CDCI3) 8: 0.93 (3H, d, J = 6Hz), 1.08-1.23 (8H, m), 1.58 (2H, m), 1.73 (2H, m), 2 59 (2H, s), 4.15 (2H, q, J = 6Hz), 4.60 (2H, s). 25 MS (APCI) m/e: 244 ([MH]+; 8%), 198(100%), 183 (68%), 168 (66%) <br><br>
IR thin film v (cm-1): 1029, 1179, 1195, 1377, 1457, 1549, 1732, 2929. C12H21NO4 calculated: C, 59.24%; H, 8.70%; N, 5.76% <br><br>
Found: C, 59.00%; H, 8.73%; N, 5.70% <br><br>
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-11- <br><br>
Lactam <br><br>
The nitro ester (2.70 g, 4.08 mmol) was dissolved in methanol (60 mL) and shaken over Raney nickel (catalytic) under an atmosphere of hydrogen gas (40 psi) at 35°C. After 18 hours the catalyst was removed by filtration through celite. The 5 methanol was removed in vacuo and the residue purified by flash chromatography (silica, ethyl acetate/heptane 1:1) to give 721 mg (39%) of a white solid. <br><br>
lH NMR 400 MHz (CDCI3) 8: 0.91 (3H, d, J = 6Hz), 0.94-1.12 (2H, m), <br><br>
1.25-1.43 (3H, m), 1.60 (2H, m), 1.71 (2H, br d, J = 16Hz), 2.21 (2H, s), 3.10 (2H, s), 5.64 (1H, brs). <br><br>
10 MS (APC1) m/e: 168 ([MH]+; 100%) <br><br>
IR thin film v (cm"1): 1254,1305,1446,1494, 1668,1693, 2910, 3219. CioH17NO calculated: C, 71.18%; H, 10.25%; N, 8.37% <br><br>
Found: C, 71.76%; H, 10.33%; N, 8.10% <br><br>
Amino Acid Hydrochloride 15 The lactam (715 mg, 4.0 mmol) was heated to reflux in a mixture of 6N <br><br>
HC1 (15 mL) and 1,4-dioxan (5 mL) After 4 hours the solvent was removed in vacuo and the solid residue recrystallized from a methanol/ethyl acetate/heptane mixture to give 664 mg (70%) of a white solid. <br><br>
!h NMR 400 MHz (d-6 DMSO) 8: 0 88 (3H, d, J = 6Hz), 1.10 (2H, m), 20 1.22 (3H, m), 1.22 (3H, m), 1.51 (2H, m), 2.43 (2H, s), 2.85 (2H, s), 7.92 (3H, brs), 12.39 (1H, br s). <br><br>
MS (APCI) m/e: 186 ([MH-HC1]+; 100%) <br><br>
Ci0H20NO2Cl calculated: C, 54.17%; H, 9.09%; N, 6.32%; CI, 15.99% <br><br>
Found: C, 54.33%; H, 9.38%; N, 6.32%; CI, 15.78% <br><br>
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-12-EXAMPLE 3 <br><br>
^C02Et o2N C02Et <br><br>
I I. J <br><br>
(ii) <br><br>
hci.h2^ co2h <br><br>
(iv) <br><br>
(i) (EtO)2 P(0)CH2C02Et, NaH, THF <br><br>
(ii) MeN02, Bu4N+F", THF, 70°C <br><br>
(iii) Raney Ni, H2, MeOH <br><br>
(iv) HC1/H20 <br><br>
g.B-unsaturated ester <br><br>
Sodium hydride (60% dispersion in oil, 1.029 g, 25.7 mmol) was suspended in dry tetrahydrofuran (50 mL) and cooled to 0°C. Triethyl 10 phosphonoacetate (5.36 mL, 27.0 mmol) was added. Once the effervescence had subsided the mixture was stirred at 0°C for 15 minutes. Cis 3,5-dimethyl cyclohexanone (3.24 g, 25.7 mmol) was then added and the mixture allowed to warm to room temperature. After 1.5 hours the solvent was decanted from the thick oil which had formed and the oil washed with diethyl ether (3 x 50 mL). The 15 decanted solvent and the ether washings were combined and washed with 2N HC1 (50 mL) followed by brine (50 mL), dried (MgS04), and the solvent removed in vacuo to give a clear oil which was used without purification. <br><br>
Printed from Mimosa <br><br>
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PCT/US98/166S2 <br><br>
-13- <br><br>
rraw^-Nitro ester <br><br>
The a,P-unsaturated ester (2.08 g, 10.36 mmol) was dissolved in tetrahydrofuran (20 mL) with nitromethane (1.12 mL, 20.7 mmol) and tetrabutylammonium fluoride (1.0 M in THF, 15.5 mL, 15.5 mmol) and the 5 resulting mixture heated to 70°C. After 18 hours the mixture was diluted with ethyl acetate (50 mL) and washed with 2N HC1 (40 mL) followed by brine (40 mL). The organic phase was separated, dried (MgSC>4), and the solvent removed in vacuo. The residue was purified by flash chromatography (silica, ethyl acetate:heptane, 1:9) to give 1.53 g (56%) as a colorless oil. <br><br>
10 !h NMR 400 MHz (CDCI3) 8: 0.80-0.98 (10H, m), 1.27 (3H, t, J = 6Hz), 1.58-1.80 (4H, m), 2.59 (2H, s), 4.15 (2H, q, J = 6Hz), 4.57 (2H, s). <br><br>
MS (APCI) m/e: 258 ([MH]+; 12%) <br><br>
IR thin film v (cm"1): 1028, 1182, 1377, 1461, 1549,1732,2954. <br><br>
Lactam <br><br>
15 The nitro ester (1.495 g, 5.8 mmol) was dissolved in methanol (60 mL) and shaken over Raney nickel (catalytic) under an atmosphere of hydrogen gas (40 psi) at 35°C. After 18 hours the catalyst was removed by filtration through celite. The methanol was removed in vacuo to give 997 mg (95%) of a white solid. <br><br>
*H NMR 400 MHz (CDCI3) 8: 0.52 (1H, m), 0.80-0.98 (7H, m), 1.51 (2H, m), 20 1.69 (4H, m), 2.20 (2H, s), 3.09 (2H, s), 6.03 (1H, br s). <br><br>
MS (APCI) m/e: 182 ([MH]+; 100%) <br><br>
IR thin film v (cm"1): 1258,1278,1324,1373, 1432,1456,1679,1693,2908, 3208. <br><br>
Ci iH19NO calculated: C, 72.88%; H, 10.56%; N, 7.73% <br><br>
25 Found: C, 72.76%; H, 10.74%; N, 7.61% <br><br>
Amino Acid Hydrochloride <br><br>
The lactam (981 mg, 5.4 mmol) was heated to reflux in a mixture of 6N HC1 (15 mL) and 1,4-dioxan (5 mL). After 4 hours the solvent was removed <br><br>
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in vacuo and the solid residue recrystallized from a methanol/ethyl acetate/heptane mixture to give 516 mg (40%) of a white solid. <br><br>
!h NMR 400 MHz (d-6 DMSO) 8: 0.47 (1H, m), 0.77-0.91 (8H, m), <br><br>
1.46-1.63 (5H, m), 2.45 (2H, s), 2.84 (2H, s), 8.00 (3H, br s), 12.37 (1H, br s). 5 MS (APCI) m/e: 200 ([MH-HC1]+; 100%) <br><br>
Cj iH22N02C1 calculated: C, 56.04%; H, 9 41%; N, 5.94%; CI, 15.04% <br><br>
Found: C, 56.00%; H, 9.40%; N, 6.09%; CI, 15.09% <br><br>
EXAMPLE 4 <br><br>
O <br><br>
(iii) <br><br>
HC1.H <br><br>
10 (i) (EtO)2 P(0)CH2C02Et, NaH, THF <br><br>
(ii) MeN02, Bu4N+F', THF, 70°C <br><br>
(iii) Raney Ni, H2, MeOH <br><br>
(iv) HC1/H20 <br><br>
15 <br><br>
q.B-unsaturated ester <br><br>
Sodium hydride (60% dispersion m oil, 1.048 g, 26.2 mmol) was suspended in diy tetrahydrofuran (50 mL) and cooled to 0°C. Triethyl <br><br>
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phosphonoacetate (4.76 mL, 23.9 mmol) was added. Once the effervescence had subsided the mixture was stirred at 0°C for 15 minutes. 3R 3-methyl cyclohexanone (2.45 g, 21.8 mmol) was then added and the mixture allowed to warm to room temperature. After 1.5 hours the solvent was decanted from the 5 thick oil which had formed and diluted with diethyl ether (50 mL). The decanted solvent was washed with water (50 mL) followed by brine (50 mL), dried (MgS04), and the solvent removed in vacuo to give a clear oil which was used without purification. <br><br>
7>am--Nitro ester <br><br>
10 The a,p-unsaturated ester (2.48 g, 13.6 mmol) was dissolved in tetrahydrofuran (20 mL) with nitromethane (1.96 mL, 27.2 mmol) and tetrabutylammonium fluoride (1.0 M in THF, 20.4 mL, 20.4 mmol) and the resulting mixture heated to 70°C. After 18 hours the mixture was diluted with ethyl acetate (50 mL) and washed with IN HC1 (2 x 25 mL) followed by brine 15 (25 mL). The organic phase was separated, dried (MgS04), and the solvent removed in vacuo. The residue was purified by flash chromatography (silica, ethyl acetate:heptane, 1:10) to give 2.43 g (73%) as a colorless oil. <br><br>
*H NMR 400 MHz (CDC13) 8: 0.78-0.98 (4H, m), 1.27 (3H, t, J = 6Hz), <br><br>
1.40-1.81 (8H, m), 2.61 (2H, s), 4.17 (2H, q, J = 6Hz), 4.58 (2H, s). 20 MS (APCI) m/e: 244 ([MH]+; 10%) <br><br>
IR thin film v(cm-l): 1027, 1097, 1155, 1190, 1378, 1457, 1549, 1732, 2929. <br><br>
Lactam <br><br>
The nitro ester (2.01 g, 8.28 mmol) was dissolved in methanol (30 mL) and shaken over Raney nickel (catalytic) under an atmosphere of hydrogen gas (40 psi) 25 at 35°C. After 3 hours the catalyst was removed by filtration through celite. The methanol was removed in vacuo and the residue purified by flash chromatography (silica, ethyl acetate) to give 902 mg (65%) of a white solid. <br><br>
Printed from Mimosa <br><br></p>
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